Treating Radiation-induced Necrosis of the Brain with Avastin

When brain tumors are treated with radiation therapy, there is always a risk of radiation-induced necrosis of healthy brain tissue. Insidious and potentially fatal, radiation necrosis of the brain may develop months or even years after irradiation.

This poorly understood side effect can occur even when the most stringent measures are taken to avoid exposing healthy tissue to harmful levels of radiation. In most cases, radiation necrosis of the brain occurs at random, without known genetic or other predisposing risk factors. The only treatment options typically available for radiation necrosis of the brain are surgery to remove dead tissue and use of the steroid dexamethasone to provide limited symptom control. But clinicians have not found a way to stop the progression of necrosis, despite having tested a range of therapies including anticoagulants, hyperbaric oxygen, and high-dose anti-inflammatory regimens.

However, recent studies at M. D. Anderson have shown that the monoclonal antibody bevacizumab (Avastin) may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed. Victor A. Levin, M.D., a professor in the Department of Neuro-Oncology and the senior researcher on the studies, said the findings suggest that radiation necrosis of the brain can be successfully managed—and perhaps even prevented—with bevacizumab or similar drugs.

The need for such a breakthrough is as old as radiation therapy for cancers in the brain. “No matter what we do or how good we do it, we know a small percentage of patients who receive radiation therapy to the central nervous system will suffer late-occurring radiation necrosis,” Dr. Levin said. “We used to think it was the dose that was causing problems. Then we did a study and found that there was little to no relation to radiation dose or radiation volume—the necrosis occurred simply by chance. So it is impossible to say which patients will develop this problem; we just have to monitor them and hope for the best.”

Like necrosis, the discovery that bevacizumab has an effect on necrosis can also be attributed to chance. Bevacizumab, a newer drug that prevents blood vessel growth in tumors by blocking vascular endothelial growth factor (VEGF), was originally approved in the United States for the treatment of metastatic colon cancer and non–small cell lung cancer. An M. D. Anderson group that included Dr. Levin decided to test the drug in patients who had VEGF-expressing brain tumors. “Some of these patients also had necrosis from prior radiation therapy, and we were struck by the positive response of those patients to bevacizumab,” Dr. Levin said. “We had never seen such a regression of necrotic lesions with any other drug like we did in those patients.” The observation prompted the researchers to design a placebo-controlled, double-blind, phase II trial sponsored by the U.S. Cancer Therapy Evaluation Program in which bevacizumab would be tested specifically for the treatment of radiation necrosis of the brain.

The trial is small, having accrued 13 of a planned 16 patients, and is limited to those with progressive symptoms, lower-grade primary brain tumors, and head and neck cancers. But the results have been unlike anything the researchers have seen before in radiation necrosis therapy. All of the patients receiving bevacizumab responded almost immediately to treatment, with regression of necrotic lesions evident on magnetic resonance images, while none of the patients receiving the placebo showed a response. The results were striking, and all of the patients who switched from placebo showed a response to bevacizumab as well. So far, responses have persisted over 6 months even after the end of bevacizumab treatment.

Side effects seen in the trial so far included venous thromboembolism in one patient, small vessel thrombosis in two patients, and a large venous sinus thrombosis in one patient. Dr. Levin is unsure whether the side effects were caused by therapy or the radiation necrosis itself. “We’re also not absolutely sure what is causing the positive effects against the radiation necrosis,” he said. “We presume it’s related to the release of cytokines like VEGF, since bevacizumab is very specific and only reduces VEGF levels. We think aberrant production of VEGF is involved with radiation necrosis of the brain, and the fact that even short treatment with bevacizumab seems to turn off the cycle of radiation damage further confirms the central role of VEGF in the process.”

The multidisciplinary research team has also postulated that radiation therapy damages astrocytes, a cell type involved in various brain functions, and causes them to leak VEGF. This leaked VEGF might then cause further damage to brain cells and further leakage of VEGF. “It gets to be a very vicious cycle,” Dr. Levin said. “The question is, is that all that’s going on?”

Dr. Levin hopes that the answers to that question and others may lead to preventive measures against radiation necrosis, beyond what is already done to control the development of radiation itself. Perhaps bevacizumab can be given in low doses before radiation or intermittently afterward to reduce VEGF levels and protect the brain from abnormally high levels of the protein. He hopes such approaches can be tested in future studies. “Just the fact that bevacizumab works has helped us understand so much more about what happens in radiation necrosis,” he said. “Everything we’ve tried up until now has been a brick wall.”

Avastin may very well be a viable option for radiation-induced necrorsis

The mechanism for cerebral radiation necrosis appears to be a result of radiation damage to vascular endothelial cells, causing endothelial cell proliferation, telangiectatic vessels and fibrinoid necrosis with accompanying perivascular exudation and edema.

Previous research findings suggest that hypoxia and its subsequent induction of vascular endothelial growth factor (VEGF), may be the primary events causing neovascularization in cerebral radiation necrosis.

Avastin blocks VEGF and causes existing microcapillaries to die. This is what is measured with the AngioRx assay, death of existing endothelial cells of microcapillaries, and associated cells. Microcapillary blood vessels run throughout the brain in close proximity to brain cells.

Some clinical work on Avastin suggests that there could be several possible mechanisms for Avastin, including potentially decreasing the oncotic pressure within the center of a necrotic tumor, which can limit the ability of the drug it is given with to be delivered into the tumor.

The oncotic pressure (or colloid osmotic pressure) is a form of osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system. Because "large" plasma proteins cannot easily cross through the capillary walls, their effect on the osmotic pressure of the capillary interiors will, to some extent, balance out the tendency for fluid to leak out of the capillaries (oncotic pressure tends to pull fluid into the capillaries).

A drop in vascular permeability induces trans-vascular gradients in oncotic and hydrostatic pressure iin blood vessels. The induced hydrostatic pressure gradient improves the penetration of large molecules (Avastin is a large molecule drug) into vessels.

It remains unclear whether Avastin is effecting a benefit on the vasculature or reactive vascularization in response to the hypoxic environment. The resolution of enhancement is primarily from removal of vascular endothelial growth factor-induced reactive vascularization, resulting in improvement of cerebral edema and neurocognitive functions.

Scientists from MD Anderson (and other institutions) have found out that they could treat radiation-induced necrosis of the brain with Avastin. Recent studies have shown that Avastin may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed.

I can see where radiation can allow the lining of the brain to become permeable to VEGF, and VEGF can induce the brain cells to make more VEGF, and self-propagating brain damage ensues. And Avastin can disable VEGF.

The MD Anderson research team postulates that radiation therapy damages astrocytes, a cell type involved in various brain functions, and causes them to leak VEGF. This leaked VEGF might then cause further damage to brain cells and further leakage of VEGF. And the ultimate question is "is that all that's going on?"

With Hyperbaric Oxygen Therapy (HBOT), wound healing requires oxygen delivery to the injured tissues. Radiation damaged tissue has lost blood supply and is oxygen deprived. HBOT provides a better healing environment and leads to the growth of new blood vessels in a process called re-vascularization. HBOT acts as a drug when 100 percent oxygen is delivered at pressures greater than atmospheric (sea level) pressure to a patient in an enclosed chamber.

If this is the case, the judicious application of Avastin can normalize the vasculature by pruning the immature vessels and fortifying the remaining ones. Normalized vasculature is less tortuous and the vessels are more uniformally covered by pericytes (in capillaries which regulate the blood-brain barrier) and basement membrane (thin sheet of fibers which lines the interior surface of blood vessels).

What dosages of Avastin are given?

M.D. Anderson researchers, who had a small placebo-controlled, double-blind, phase II trial on this, thought giving Avastin in "low doses" before radiation or intermittently afterward to reduce VEGF levels and protect the brain from abnormally high levels of the protein.

Avastin, at a dose of 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks, has been shown to reverse neurocognitive deficits, cerebral edema and enhancement on MRI in patients having confirmed radiation necrosis.

The "low doses" has me thinking that Avastin has turned up as a treatment in advanced macular degeneration (AMD), although as Lucentis, a cheaper version of Avastin and essentially the same drug. Ophthalmologists discovered minute injections of Avastin were extremely effective in treating AMD, which involves excess blood vessel formation in the eye.

The "cost" of small injections to break up those blood vessels is about $50 a shot. Genentech then developed a variation of Avastin called Lucentis, ran a clinical trial testing it in AMD patients, got it approved by the FDA and began charging nearly $2,000 for the shots, which are needed monthly.

I was asked recently, if Avastin for radiation-induced necrosis involved direct injection of "small" amounts into the damaged brain cells. If so, then neurologists can do the same thing ophthalmologists did, break open the vials sold for cancer and do it on the cheap rather than wait for Genentech to get an FDA indication for a variant of the drug, and then charge a higher price.

If you have to make a 20% co-pay on a $2,000 shot, it's $400. If you have to pay the entire price of a $50 shot, it's $50. Even if Medicare or the private insurer didn't want to pay for the off-label use, you're still better off financially.

It seems to me that a medical oncologist, radiation oncologist or a neurologist could give this medication. I know of a few neruosurgeons who are giving this to some of their patients with confirmed radiation-induced necrosis.

Avastin (bevacizumab) is an anti-angiogenic agent and a natural cadidate for blocking vascular endothelial growth factor (VEGF) that produces leaky capillaries which are largely responsible for the edema and symptoms of radiation necrosis in the brain. A number of case reports and series have been published.

Seeing responses in patients treated with Avastin for their cancers, led to a placebo-controlled, double-blind, phase II trial sponsored by the U.S. Cancer Therapy Evaluation Program in which Avastin would be tested specifically for the treatment of radiation necrosis of the brain.

The trial (Gonzalers et al) was limited to those with progressive symptoms, lower-grade primary brain tumors, and head and neck cancers. All of the patients receiving Avastin responded almost immediately to treatment, with regression of necrotic lesions evident on magnetic resonance images (MRI), while none of the patients receiving the placebo showed a response.

The results were striking, and all of the patients who switched from placebo showed a response to Avastin as well. So far, responses have persisted over 6 months even after the end of Avastin treatment. However, more studies are clearly needed.

A recent series notes: "In children with pontine gliomas, Avastin may provide both therapeutic benefit and diagnostic information. More formal evaluation of Avastin in these children is needed."

Another one concludes: "Avastin, alone and in combination with other agents, can reduce radiation necrosis by decreasing capillary leakage and the associated brain edema. Our findings will need to be confirmed in a randomized trial to determine the optimal duration of treatment."

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